Trials Conducted in Unresectable Locally Advanced Lung Adenocarcinoma Show Path for Treatment

Zofia Piotrowska, MD

Multiple treatment options exist for patients with unresectable locally advanced lung adenocarcinoma. Zofia Piotrowska, MD, assistant professor, Harvard Medical School, Massachusetts General Hospital, examined the options during a Targeted Oncology Case-Based Peer Perspectives event.

Targeted Oncology^TM: Would you consider using immunotherapy in patients with EGFR- or ALK-positive tumors?

PIOTROWSKA: There is some hot debate about how those patients should be treated. Especially as we’re getting the EGFR status more routinely for [patients who are] earlier stage, that’s been a concern of mine for the patients with EGFR mutations if you give them durvalumab [Imfinzi] and then they recur. I had [a patient who] recurred in the brain. I wanted to give them osimertinib [Tagrisso], but I was also worried about the increased risk of pneumonitis [that can occur] when someone gets immunotherapy and goes on to a tyrosine kinase inhibitor [TKI].

Do you consider sequential treatment if you don’t think patients are eligible for concurrent treatment?

At our institution [Massachusetts General Hospital], we’ve generally moved away from those [adjuvant] cycles of chemotherapy, maybe even before the PACIFIC trial data [NCT02125461], but especially now in light of those results. [We] have been moving straight on to treatment with durvalumab.

The data have been mixed, although the worry is that patients are not getting systemic doses of chemotherapy with weekly carboplatin/paclitaxel. But in my experience, many of these patients are not fit, so to get them through weekly carboplatin/paclitaxel is enough, and then it doesn’t [seem] great to give them full-dose carboplatin/paclitaxel after the end of chemoradiotherapy.

For the patient with nonsquamous disease, particularly for fit patients, I have used carboplatin/pemetrexed [Alimta]. For the [patients who are more frail], regardless of histology, I find myself giving a lot of weekly carboplatin/paclitaxel. That’s probably my most common regimen. In recent years, I would say rarely, but sometimes I’d use the EP 50-50 regimen [etoposide/cisplatin] as well for the patients with squamous disease where it fits.

Do you find that most patients are eligible for durvalumab following the end of chemoradiotherapy?

In other settings, I have had some people who say, “There is a subset of these patients who aren’t eligible.” But my experience has [not] been the same. Generally, [for] people who get through chemoradiotherapy…primary progression after chemoradiotherapy is uncommon. I think I’ve only seen it once, and it was bad when it happened. That is a requirement for patients to go on to durvalumab. It sounds [as though] that’s not a common problem that any of us are encountering.

Can you please discuss the data behind durvalumab?

PACIFIC was a phase 3 randomized, double-blind study looking at patients with stage III unresectable non–small cell lung cancer.¹ These patients didn’t progress following definitive chemoradiotherapy with platinum-based chemotherapy, and the chemotherapy regimens that I discussed [such as paclitaxel, etoposide, or pemetrexed] were allowed. After chemoradiotherapy, for staging, patients had to prove that they hadn’t progressed. And then they were randomized 2:1 to either durvalumab every 2 weeks for up to 12 months or to placebo. The total size of the study was about 700 patients. The coprimary end points were progression-free survival [PFS] and overall survival [OS].

One key point was the study required patients to be randomized within 42 days of chemoradiotherapy. A historical footnote is [that], originally, the study started with a shorter time frame to randomization. It was 14 days, [but the investigators] had to loosen that based on the fact that they were having a hard time getting patients on to the study and randomized within that time frame. There was a subgroup in a later breakdown by time to treatment that showed there was some benefit to an earlier start of treatment.

What did the updated efficacy results for this study reveal?

The updated data were presented at the European Society for Medical Oncology [ESMO] Virtual Congress recently.2 [It was] a 4-year update with a median PFS of 17.2 months for durvalumab versus 5.6 with placebo, with a hazard ratio of 0.55 [95% CI, 0.44-0.67].

The landmark analysis [demonstrated that] 49.6% of patients [treated with durvalumab were] alive at 4 years. There was continued nice separation of the curves for OS with a hazard ratio of 0.71 [95% CI, 0.57-0.88]. The medians OS was 29.1 months in the placebo arm and 47.5 months in the durvalumab arm.

The updated data from ESMO looked at the different subgroups. The OS data for EGFR mutation status—the study did enroll some patients with EGFR mutations, but the number of patients was still quite small—showed that there was less benefit in EGFR-positive tumors.

The prespecified breakdown in this study was to look at PD-L1 status of greater or less than 25%. There was [OS] benefit if you look at the overall study population, which was the primary end point. With more follow-up, there is less benefit in terms of OS in the less-than-25% PD-L1 group.

What’s noteworthy and [received] a lot of attention is [that] when this was submitted for approval to the European Medicines Agency, they asked for a post hoc analysis to be done not just looking at the 25% breakdown but [also] including patients with less than 1% expression or higher than 1%. What they saw was that the patients who had less than 1% PD-L1 expression didn’t have a benefit [in terms of OS]. That led to the approval of durvalumab for patients with greater than 1% PD-L1 expression in Europe.³

There was a lot of debate about that at the time because that was an unplanned analysis of the study. If you look at the overall population, there was a benefit seen in the total population. I know even some European oncologists weren’t happy that approval excluded patients with less than 1% expression.

What do you think of the results of the poll?

Most commonly it’s about 3 weeks or between 3 and 5 weeks or so. That’s my experience, too. It’s [difficult] to get people on in a shorter time span than that just to get organized. [There’s] the end of chemoradiotherapy, then a bit of time for recovery, and getting a CAT scan for restaging. [After all of that], then they can get started. It’s a lot of steps to coordinate in 14 days. That’s been a big hurdle, but I certainly try to get them on therapy within a short time frame if I can.

How did the difference in when patients started treatment affect their survival?

The subgroup analysis looked at these 2 groups and specifically at when patients started treatment. There was a small number of patients in this study who started durvalumab within 14 days…compared with those patients who started after 14 days. I presume that in order to start within 14 days, you have to have been a rock star patient throughout the entire course to be able to get on therapy so quickly.

There was a trend toward an improvement in PFS in the patients who started earlier. I think those data have been noteworthy, and it seems [as though the data have] made it on to everyone’s radar. Fourteen days is a hard timeline to fulfill, but I think there’s an impetus to try to start as soon as we can for these patients. There’s a sense that the longer you wait, the harder it is and there is less benefit. [One of the hypotheses that has] been thrown around…is it that the immunogenicity of a tumor right after chemoradiotherapy is highest and therefore the benefit might be greatest in those patients.

What helps you decide on sequencing after immunotherapy for patients with late-stage unresectable lung cancer?

One of the challenges of immunotherapy is that the half-life is so long that it lasts in the patients’ system for a long time.…This patient I had seen who had an EGFR mutation had [received] durvalumab and then presented with brain metastases. And now what do you do? Osimertinib is the best option for them in terms of the [central nervous system] disease, but there is also some concern that the patient had stopped durvalumab within a short time frame [of next therapy]. We ended up giving him osimertinib and watching closely, and he did OK. But [there is a risk of] pneumonitis when osimertinib is given after immunotherapy.

I think they’re both expensive therapies, durvalumab and osimertinib. I have had many colleagues who say until we see [negative] data for the EGFR-positive population, there is a proven OS benefit for durvalumab, and I don’t want to withhold it.

The important thing to know here is that if you do give immunotherapy, you have to be cautious if you end up putting the patient on a TKI afterward. And certainly, those patients need to be watched closely. I would have a low threshold for stopping immunotherapy if it seems [as though] they [were] having any issues or if there [was] any concern about recurrence.

How did the toxicity profile of durvalumab affect patients on the PACIFIC trial?

One of the concerns with this study, and I think now we all feel fairly comfortable with this, [was the rate] of pneumonitis after thoracic radiation. What was reassuring was that although…about a quarter to [one-]third of patients [were] having pneumonitis in these 2 arms, the rates of grade 3 or 4 pneumonitis were reassuringly low in both arms, at 3.4% versus 2.6% [for durvalumab and placebo, respectively].

My experience in the clinic is that [data] may have been a bit lower than what I’ve seen [in real-world populations]. I’ve had a few patients who have had pneumonitis, so I think the real-world data [are] maybe not always the same as [in] a highly selective clinical trial population. But it hasn’t been that prohibitive of a concern the way that we might have been worried about.

What do the National Comprehensive Cancer Network (NCCN) guidelines say about durvalumab in this setting?

Right now, the recommendation from the NCCN guidelines is to consider durvalumab for these patients.⁴

The NCCN guidelines deleted the recommendation for 2 cycles of full-dose chemotherapy if patients had not received full-dose chemotherapy with radiation. In general, consolidation is an option. Chemotherapy is still left in the NCCN guidelines as an option for patients who cannot get durvalumab. But generally, it’s reasonable to consider going straight to durvalumab for the patients who complete chemoradiotherapy, even if it’s with weekly carboplatin/paclitaxel, particularly given the fact that they are going on to another therapy.

_References:

_{1. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. N Engl J Med. 2017;377(20):1919-1929. doi:10.1056/NEJMoa1709937}

_{2. Faivre-Finn C, Vicente D, Kurata T, et al. Durvalumab after chemoradiotherapy in stage III NSCLC: 4-year survival update from the phase III PACIFIC trial. Ann Oncol. 2020;31(suppl 4):S1142-S1215. doi:10.1016/j.annonc.2020.08.2281}

_{3. European Commission approves Imfinzi for locally-advanced, unresectable NSCLC. News release. AstraZeneca. September 24, 2018. Accessed November 23, 2020. bit.ly/3nPexxN}

_{4. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 8.2020. Accessed November 23, 2020. bit.ly/30sRU9e}